Report Biochem

Biochemical transformation of bacterial lipopolysaccharides
by acyloxyacyl hydrolase reduces host injury and promotes
recovery
Received for publication, August 4, 2020, and in revised form, October 22, 2020 Published, Papers in Press, October 26, 2020, DOI 10.1074/jbc.REV120.015254
Robert S. Munford1,
*, Jerrold P. Weiss2
, and Mingfang Lu3,
*
From the 1
Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland, USA,
the 2
Inflammation Program, University of Iowa, Iowa City, Iowa, USA, the 3
Department of Immunology and Key Laboratory of
Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai, 论文帮助/论文写作服务/负担得起我及时提交我最好的质量 – China
Edited by Chris Whitfield
Animals can sense the presence of microbes in their tissues
and mobilize their own defenses by recognizing and responding
to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses
may kill the invaders, yet the host animal may fail to restore
homeostasis if the stimulatory microbial structures are not
silenced. Although mice have many mechanisms for limiting
their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required
to extinguish LPS sensing in tissues and restore homeostasis.
We review recent progress in understanding how this enzyme,
acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus
to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps
stimulatory LPS from entering the bloodstream.We also discuss
how AOAH may increase sensitivity to pulmonary allergens.
Better appreciation of how host enzymes modify LPS and other
MAMPs may help prevent tissue injury and hasten recovery
from infection.
Animals can recognize and respond to bacteria that invade
their tissues by sensing the invaders’ MAMPs. Pro- and antiinflammatory cytokines and other mediators are produced,
neutrophils and other leukocytes are recruited to the infected
site, blood flow to the tissue increases, and increased vascular
endothelial permeability allows influx of antibodies, complement, and other molecules from the bloodstream into the tissue. Both extracellular (e.g. complement and antibodies) and intracellular mechanisms contribute to bacterial killing. The
inflammatory response may also produce tissue injury and lead
to harmful immunosuppression.
Although these features of the antibacterial host response
are well-understood, much less is known about how the inflammatory process resolves, tissue injury and prolonged immunosuppression are avoided, and normal MAMP responsiveness is
restored. Recent studies have shown that lipid mediators can
help resolve inflammation following trauma (1, 2), but the studies reviewed here provide evidence that, if infection is the inciting event, it is also necessary to eliminate or inhibit the stimulatory MAMP(s). Insight into this aspect of recovery from
MAMP-induced inflammation has come from studying how
mice silence lipopolysaccharide (LPS, endotoxin), a potent
Gram-negative bacterial MAMP that has long been implicated
in the pathogenesis of infection-induced inflammation, sepsis,
and chronic diseases (3, 4).
As Lewis Thomas wrote in The Lives of a Cell (4), “The
Gram-negative bacteria … display lipopolysaccharide molecules in their walls, and these macromolecules are read by our
tissues as the very worst of bad news … . There is nothing
intrinsically poisonous about endotoxin, but it must look awful,
or feel awful, when sensed by cells.” In fact, many host molecules can prevent cells from sensing LPS: anti-LPS antibodies,
proteins that bind and sequester LPS (bactericidal permeability-increasing protein (5), lactoferrin, cathelecidin, and plasma
lipoproteins), an intracellular phosphatase (6), and others (7).
Remarkably, none of these molecules—alone or together—can
completely silence LPS in mice, and bacteria do not usually
destroy their own molecules, especially large macromolecules
(8). Instead, LPS silencing is accomplished by a highly conserved host lipase, acyloxyacyl hydrolase (AOAH). Named for
its chemical sites of action (9), AOAH removes from LPS the
fatty acyl chains that are essential for its immunostimulatory
activity and transforms this potent agonist into an effective LPS
antagonist.
Here we review how LPS is sensed by animal cells, the importance of LPS acylation in determining the agonistic potency of
LPS, the structure and enzymatic properties of AOAH, and evidence that AOAH plays significant roles in both moderating
and terminating host inflammatory responses to LPS and
Gram-negative bacteria. Recent findings have pointed to important roles for AOAH in limiting inflammatory responses to
Gram-negative bacteria, restoring normal immune responsiveness after LPS exposure, preventing stimulatory LPS from
entering the bloodstream, and reducing the agonistic activity of
intestinal LPS. We then describe human genetic evidence that
AOAH may be an “essential” gene and studies that have identified a unique trans (cross-chromosomal) regulatory mechanism and potential associations with colitis and asthma.
Sensing LPS
The LPS produced by most Gram-negative bacteria has a
polysaccharide chain of variable length that is anchored to the
* For correspondence: Robert S. Munford, munfordrs@niaid.nih.gov; Mingfang Lu, mingfanglu@fudan.edu.cn.
17842 J. Biol. Chem. (2020) 295(51) 17842–17851
Published in the U. S. A.
REVIEWS
This is an Open Access article under the CC BY license.
bacterial outer membrane by the lipid A moiety (10) (Fig. 1).
Animal cells sense extracellular LPS through the receptor
known as MD2-TLR4 (myeloid differentiation factor 2–Tolllike receptor 4). Other host proteins (mainly LPS-binding protein (LBP), phospholipid transfer protein (11, 12), soluble and/
or membrane CD14 (sCD14 and/or mCD14), and albumin
(13)) can extract individual LPS molecules from bacterial membranes and transfer them to cell surface (or endosomal) MD-2–
TLR4. (Fig. 2A) Activation occurs most potently (i.e. at picomolar concentrations (14)) when LPS molecules with hexaacyl
lipid A (Fig. 1) form ternary complexes with MD-2–TLR4.
These ternary complexes form stable dimers that promote assembly of multiprotein intracellular signaling complexes and
initiate intracellular signal/transduction (15). MyD88-dependent signaling is initiated by activated receptor complexes at
the cell surface, whereas MyD88-independent (TRIF-dependent) signaling is triggered by activated LPS–MD-2–TLR4 receptor complexes within endosomes (16). Together, these signals initiate inflammatory cellular and humoral responses to
kill the invading bacteria.
From stimulus to inhibitor: the importance of LPS
acylation
Most of the aerobic Gram-negative bacteria that inhabit mucosal surfaces and/or commonly cause disease in animals produce LPS that has hexaacyl lipid A (3). In Escherichia coli LPS,
for example, myristoyl and lauroyl chains are attached via acyloxyacyl linkages to the hydroxyl functions of two of the four
diglucosamine-linked 3-hydroxymyristoyl chains (Fig. 1). Some
other Gram-negative aerobes and most Gram-negative anaerobes (e.g. Bacteroides species), produce pentaacyl LPS, a
weaker MD-2/TLR4 agonist (17) that may inhibit hexaacyl LPS
signaling (18). The fatty acid composition can vary both within
and between species (19); in Vibrio cholerae and Pseudomonas
aeruginosa, for example, secondary acyl chains can be hydroxylated (20, 21).
AOAH cleaves only the acyloxyacyl linkages, removing the
secondary (or “piggyback”) acyl chains to produce pentaacyl or
tetraacyl lipid A (Fig. 1). An early study found that human
AOAH preferentially removed shorter (laurate . myristate),
and nonhydroxylated (laurate . 2-OH–laurate) secondary
chains (22). The resulting tetraacyl LPS still binds the MD-2–
TLR4 receptor with comparable affinity, but the probability
that the tetraacyl LPS–MD-2–TLR4 complex will form a stimulatory ternary complex is markedly reduced (23–25). This
may reflect ligand acylation-dependent differences in the ability
of the resulting ternary complexes to form the stable higherorder structures required for signal transduction (15).
The extraction and transfer of LPS monomers from LPS-rich
surfaces (e.g. the bacterial outer membrane) to CD14 is necessary not only for efficient delivery of activating (hexaacyl) LPS
to MD-2–TLR4 but also to present the LPS as a substrate for
AOAH (26) (Fig. 2B). The apparent “Km” is 100-fold lower for
transfer of the LPS monomer from sCD14 to MD-2–TLR4
than it is for deacylation by AOAH of LPS bound to sCD14
(26). However, the higher levels of sCD14 versus MD-2 often
found in tissues suggest that monomeric LPS:sCD14 intermediates could accumulate, followed by AOAH action and delivery
of much less stimulatory (“ stimulatory”) AOAH-deacylated
LPS (dLPS) to MD-2–TLR4 (Fig. 2B). Taken together, these
properties seem most compatible with the ability of LPS at
picomolar concentrations to activate potent immune responses
acutely followed by a subsequent dLPS-assisted return to “resting” conditions.
Deacylation by AOAH reduces the stimulatory potency of
hexaacyl LPS molecules by as much as 50–100-fold (27–30).
Moreover, dLPS can competitively reduce binding of hexacyl
LPS to MD-2–TLR4 and thereby inhibit formation of the hexaacyl LPS–MD-2–TLR4 ternary complexes needed to activate
Figure 1. AOAH removes secondary acyl chains from LPS. E. coli LPS and lipid A are shown. The diglucosamine backbone is phosphorylated at 1 and 49,
and four primary 3-hydroxy fatty acyl chains are attached to the backbone in ester or amide linkage. Secondary acyl chains (red), usually myristate or laurate,
are attached via acyloxyacyl linkage to two of the primary chains. Six acyl chains and both phosphates are required for optimal recognition by the MD-2–TLR4
receptor on animal cells. AOAH cleaves the acyloxyacyl linkages (arrows), converting stimulatory hexaacyl LPS into antagonistic tetraacyl LPS.
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signaling (Fig. 2B). dLPS inhibition of LPS stimulation has been
demonstrated in vitro using human umbilical vein endothelial
cells (28, 31), human neutrophils (30), and murine macrophages and splenocytes (29). Even substoichiometric concentrations of dLPS may inhibit LPS signaling (32). In addition,
dLPS can compete with LPS at each of the preceding steps
involved in presenting LPS to MD-2–TLR4 (33) (i.e. by engaging LBP and/or CD14) (34). Teghanemt et al. (35) and Gioannini et al. (25, 26) demonstrated directly that dLPS interacts
with MD-2 to form a complex with markedly reduced ability to
activate TLR4, therefore acting as an MD-2–TLR4 antagonist.
Activation of LPS-sensing cytosolic caspases by LPS also
appears to depend upon the acylation state of LPS (36–38). An
effect of AOAH-dependent LPS deacylation on regulating the
activation of this cytosolic recognition/response system has not
been reported.
Independent evidence for the importance of lipid A acylation
in host–Gram-negative bacteria interactions has come from
Gram-negative pathogens that can make hypoacylated (,6 acyl
chains) LPS (39). Intracellular Shigella flexneri bacteria can
avoid activating an inflammatory response by reducing LPS
acylation (40), Salmonella typhimurium may produce a pentaacyl LPS with low stimulatory activity (41), Francisella spp.
make tetraacyl LPS (42), and Yersinia pestis switches production from hexaacyl to tetraacyl LPS at mammalian body temperatures and prevents mobilization of TLR4-dependent host
defenses (43, 44). For these intracellular bacteria, producing
hypoacyl lipid A/LPS is an immune evasion mechanism.
As will be discussed below, AOAH-mediated transformation
of LPS from hexaacyl to pentaacyl or tetraacyl can be antiinflammatory (blunting LPS signaling via TLR4) as well as restorative (reestablishing normal host responsiveness to infection by inactivating stimulatory LPS). First, we summarize
some of the enzyme’s important features.
AOAH biosynthesis, structure
AOAH is a glycoprotein with Mr = 52,000–60,000 (45, 46).
Its two potential subunits are joined by a single disulfide bond
before the precursor peptide is cleaved to form the mature protein (46). The smaller subunit is a member of a protein family
that includes several proteins that act at lipid-water or lipid-air
interfaces or as cofactors for lysosomal hydrolases (47). The
larger subunit (;50,000 Da) is a GDSL lipase; the best-characterized member of this family is platelet-activating factor acetylhydrolase (48). When AOAH cDNA was expressed in cultured fibroblasts, much of the precursor protein was secreted,
internalized by other cells, and cleaved within an acidic endosomal-lysosomal compartment to form the mature enzyme (49),
which was more active toward LPS than was the precursor
(48, 49).
Analysis of the crystal structure led Gorelik et al. (48) to conclude that “LPS binds to AOAH with its fatty acid tails covered
by the hydrophobic pocket formed by the saposin and catalytic
domains and a secondary (acyloxyacyl) chain buried in the
hydrophobic tunnel at the active site.” A space-filling model
resembles the “fingers in glove” appearance of lipid A inserted
into MD-2 (50).
The DNA sequence that encodes AOAH has been found in
all vertebrates studied except fish, which produce a TLR4 that
is not activated by LPS (51), and also in many invertebrates
(52). It is likely that AOAH was the LPS esterase originally
Figure 2. A, soluble cofactors enable LPS signaling. A single Gram-negative bacterium or outer membrane vesicle can contain .106 LPS molecules, all present
in the outer leaflet of the outer membrane. 1, LBP binds to membrane particles containing hexaacyl (stimulatory) LPS and initiates the extraction and transfer
of LPS monomers to sCD14 or mCD14. 2, LPS can be exchanged between sCD14 and mCD14. Either sCD14 or mCD14 can transfer the LPS monomer to MD2-
TLR4 (3), which initiates TLR4 signaling following formation and dimerization of LPS-MD2-TLR4 ternary complexes (see text for more details) (4). B, AOAH
deacylates LPS. 5, sCD14 can transfer LPS to mCD14 or to extracellular AOAH, which removes the two secondary acyl chains (red) to produce tetraacyl
( stimulatory, antagonistic) dLPS. 6, dLPS is transferred back to sCD14 (no protein-free form of either hexaacyl or tetraacyl LPS is detected). sCD14 can transfer the tetraacyl dLPS to MD2-TLR4, but this ternary complex, unlike that of hexaacyl LPS-MD-2–TLR4 (Fig. 2A), does not form a stable dimerized ternary complex that can initiate signaling. 7, dLPS may also compete with hexaacyl LPS for binding MD2-TLR4. 8, mCD14 can promote uptake of LPS into an endosomal
compartment, where it can be deacylated by AOAH.
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described in the slime mold Dictyostelium discoideum (53),
which also has lipid A–deacylating amidases and uses Gramnegative bacteria as a foodstuff (54). Although AOAH can act
on other lipids, including phospholipids (55) and some bacterial lipoproteins (48), its activity toward lipid A/LPS is unique.
Cellular sources of AOAH
Although AOAH was intially found in neutrophils (9), cellular levels of AOAH are often lower in circulating and exudate
neutrophils than in monocytes/macrophages, hepatic Kupffer
cells (56), immature dendritic cells (57, 58), and NK cells.
AOAH expression has also been found in mucosal ILC1 cells,
which are closely related to NK cells but lack granulysin and
perforin and have a genomic “superenhancer” region that
includes part of the AOAH gene (59). Naive T cells just released
from the thymus express AOAH mRNA along with mRNAs for
complement receptors, IL-8, and TLR1 (60), consistent with a
role in antimicrobial defense.
Macrophages internalize LPS into an endosomal compartment that contains AOAH (61); mCD14 can enable this uptake
(62) (Fig. 2B). LPS deacylation occurs over several hours and
can be inhibited by agents that prevent endosomal acidification
(61), in keeping with the enzyme’s low pH optimum for LPS
deacylation in vitro. In general, cellular and secreted levels of
AOAH increase for 1 or 2 days after the cells are stimulated
with LPS or other agonists. Murine peritoneal macrophages
greatly increased AOAH synthesis when they were stimulated
in vitro with interferon-g or LPS (63). Murine alveolar macrophages also constitutively express little AOAH, but 18 h following stimulation with LPS, either in vivo or ex vivo, they
increased AOAH mRNA expression 40–100-fold (64). According to a recent comparison of mRNA abundance in murine and
human brain cells, AOAH mRNA is much more highly
expressed in human than in murine microglia (65). AOAH
mRNA abundance increased in embryonic murine microglia,
provided that the mother had received a standard (not germfree) diet (66), pointing to a possible role for AOAH or translocated LPS (see below) in embryonic development.
Janelsins et al. (67) reported that resident colonic dendritic
cells (DCs) express more AOAH than do DCs in other murine
organs; AOAH mRNA abundance decreased when antibiotics
were added to the drinking water and was barely detectable in
colonic DCs from TLR42/2 mice. AOAH activity also increased
when murine marrow–derived DCs were treated with LPS (57).
Like peritoneal macrophages, the marrow-derived DCs deacylated the LPS in phagocytosed E. coli (57). Murray et al. (58)
recently reported that circulating myeloid precursor DCs
increased AOAH mRNA abundance 4-fold in people living
with (latent) HIV.
There is an important exception to the generalization that
AOAH is mainly produced by myeloid or lymphoid cells. When
radiolabeled AOAH cDNA was used to perform a Northern
blot analysis of mouse tissues, the greatest signal came from the
kidney (68). In situ hybridization revealed that AOAH mRNA
was localized to proximal tubule cells; further study found that
mice and humans secrete mature AOAH into the urine. The
AOAH could be taken up by bladder cells and deacylate LPS. A
protective role for AOAH seems likely in the urinary tract,
where E. coli and other aerobic Gram-negative bacteria are the
most common pathogens.
AOAH can also deacylate LPS extracellularly (Fig. 2B). In ex
vivo studies of a sterile inflammatory exudate induced in rabbits, Weinrauch et al. (69) showed the presence of AOAH in
both inflammatory cells (macrophages . neutrophils) and in
cell-free inflammatory fluid. Conversion of LPS to dLPS was
demonstrable using either purified LPS or intact E. coli containing metabolically prelabeled LPS; it was greatest when macrophages were present (70).
In summary, although AOAH has been studied most often in
phagocytes that respond to LPS and contribute to innate antibacterial defense—macrophages, DCs, and neutrophils—it is
also produced by Kupffer cells, NK cells, ILC1 cells, recent thymic immigrant T cells, microglia, and renal proximal tubule
cells. Cell stimulation is generally followed by gradual increases
in AOAH abundance from low constitutive levels to maximal
production within a day or two.
AOAH prevents, moderates, and terminates responses
to LPS
Evidence that AOAH influences how animals respond to
LPS and Gram-negative bacteria has come from studies in
transgenic AOAH-producing (71) and Aoah2/2 (57) mice. Significant roles have been found for preventing hexaacyl LPS
from entering the bloodstream from a tissue site or the intestine, moderating and shortening the inflammatory response to
Gram-negative bacteremia and pulmonary challenge, and terminating the immunosuppressive period of cellular reprogramming (“tolerance”) that follows exposure to LPS.
AOAH prevents stimulatory LPS from entering the
bloodstream
The pathological consequences of Gram-negative bacteremia and endotoxemia have ranged from metabolic diseases
to septic shock and death. Like Gram-negative bacteria, LPS
moves via lymphatics from a subcutaneous injection site to
draining lymph nodes and continues via lymphatics into the
bloodstream. AOAH-dependent deacylation, largely carried
out by macrophages, can inactivate most of the LPS before it
reaches the circulation. When Aoah2/2 and Aoah1/1 mice
were compared, subcutaneously injected LPS induced more robust proliferation of B cells and plasmablasts in draining lymph
nodes of Aoah2/2 mice and increased their blood IgM and
IgG3 levels for weeks (72, 73), confirming that AOAH participates in limiting responses to LPS even before the LPS molecules reach draining lymph nodes and the bloodstream.
Many investigators have studied the role of microbiotaderived LPS (endotoxemia) in the pathogenesis of diseases such
as atherosclerosis, diabetes mellitus, metabolic syndrome, and
others (74–77). There is evidence for translocation of stimulatory LPS into the bloodstream from the colon (78), where intestinal AOAH is most abundant (79). Qian et al. (79) obtained
indirect evidence for AOAH-dependent LPS inactivation by
measuring TLR4-stimulating activity using a TLR4 reporter
cell line (80). In stool, mesenteric lymph nodes, plasma, and
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J. Biol. Chem. (2020) 295(51) 17842–17851 17845
lung, TLR4 stimulation was greater in Aoah2/2 mice than
in Aoah1/1 littermate controls. The stimulatory activity decreased when polymyxin B was added to inhibit LPS or when
antibiotics that kill aerobic Gram-negative bacteria were
added to the drinking water to reduce hexaacyl LPS abundance in the intestine (79).
Protection from systemic stimulation by translocated intestinal LPS has often been attributed to the ability of intestinal alkaline phosphatase to inactivate LPS by removing one
or both phosphates from lipid A (Fig. 1) (81, 82). With the
recent discovery that certain primary (glucosamine-linked)
acyl chains must be removed from lipid A before intestinal
alkaline phosphatase can cleave either of the lipid A phosphates (Fig. 1) (83), AOAH became the most likely host
mechanism for reducing the stimulatory potency of LPS molecules in the intestine by modifying lipid A structure. As
noted above, its production by colonic DCs increases with
hexaacyl LPS exposure.
As reported by d’Hennezel et al. (84), the net impact of the
abundant Bacteroides (largely pentaacyl and monophosphoryl (85)) LPS in the human colon is to decrease TLR4 signaling by competing with TLR4-activating hexaacyl LPS (18,
86). Although Bacteroides genus tetraacyl lipid A was also
found in the colon, the extent to which AOAH contributes to
reducing levels of stimulatory intestinal LPS and generating
increased levels of competing, weakly agonistic dLPS is not
known. Colonic AOAH may help prevent excessive LPSinduced tolerance in DCs (see below), inflammation stimulated by excess hexaacyl LPS (as may accumulate during
colitis (80)), and translocation of hexaacyl LPS into the bloodstream (79).
AOAH decreases LPS-induced inflammation in tissues
Although AOAH may be synthesized slowly after the onset
of infection or LPS challenge, the enzyme can play a significant
role in preventing potentially harmful consequences of the
inflammatory response. For example, AOAH shortened the duration of LPS– or Klebsiella pneumoniae–induced pulmonary
inflammation in models of experimental pneumonia (64). In
the Aoah2/2 animals, persistent LPS stimulated alveolar macrophages and epithelial cells to recruit more neutrophils to
the lung, greatly delaying recovery and decreasing survival.
AOAH has also improved survival from experimental Gramnegative bacteremia (71), hastened recovery in bacteremia survivors (87), and moderated LPS-induced hepatic inflammation
(56, 71, 88).
In addition to the tissue injury that can be produced by excessive host responses to infection, tissue damage can be
caused when host cells produce potentially toxic mediators,
such as oxidized phospholipids and lysophospholipids. For
example, dead cells can release oxidized phosphatidylcholine
that mCD14 can deliver into DCs and activate an inflammatory response (89). Although AOAH can deacylate phospholipids and lysophospholipids in vitro (48, 55), a role for the
enzyme in inactivating these or other lipids in vivo has not
been established.
AOAH shortens endotoxin tolerance/immunosuppression
As if to prevent damage from “friendly fire,” the initial
inflammatory response to LPS is typically followed by a state
of tolerance (cellular reprogramming) (90–92) during which
many of the host animal’s pro-inflammatory responses to
sensing LPS are diminished while some anti-inflammatory
responses increase. Host defenses are typically weaker during
this period of relative immunosuppression. Homeostasis is
usually restored within a few days, and the animal’s responses
to subsequent LPS exposure (or microbial invasion) return to
normal.
When Lu et al. gave a small intraperitoneal dose of LPS to
Aoah2/2 mice, however, the animals remained tolerant for
many weeks and were more likely than Aoah1/1 mice to die
from live E. coli challenge (93). Further study found that stimulatory LPS molecules persisted for many weeks in the peritoneal
cavities of Aoah2/2 mice and continued to tolerize macrophages there (94). AOAH was required to end the tolerant state
(Fig. 3). It seems unlikely that long-term epigenetic changes
prolonged tolerance because the tolerant peritoneal macrophages quickly regained responsiveness when they were transferred to a nontolerant, Aoah1/1 animal (94).
In keeping with these findings in living mice, Mages et al.
(95) found large AOAH increases in LPS-tolerant marrow macrophages in vitro. In addition, stimulating cells with one TLR
agonist may invoke tolerance to others (“cross-tolerance”),
plausibly a general mechanism for reducing cell activation during recovery from infection. Lu et al. (57) found that AOAH activity in murine DCs increased when the cells were treated not
only with LPS (TLR4) but also with TLR agonists CpG oligonucleotides (TLR9) and Micrococcus luteus (TLR2)—but not with
inflammatory cytokines. AOAH production may increase during tolerance elicited by many different bacterial MAMPs.
Another role for AOAH in the regulation of LPS-induced tolerance was reported by Janelsins et al. (67), who found that
CD1031CD11b1ALDH2 colonic dendritic cells express much
more AOAH than do DCs in other organs. Aoah2/2 colonic
DCs expressed more features of tolerance—less IL-6 production, less Th17 polarization, and greater Treg cell induction—
than did colonic DCs from Aoah1/1 mice.
There is also evidence that intestinal AOAH can influence
tolerance to pulmonary allergens (79). Previous studies had
found that gut-derived or intratracheally administered hexaacyl
LPS and other TLR agonists can decrease allergic TH2 responses linked to the development of asthma, whereas gutderived pentaacyl LPS may permit them (96–99); in other studies, low LPS doses elicited TH2 allergic responses (e.g. IL-4,
IL-5, and IL-10) when mice were challenged with house dust
mite (HDM) extract, whereas high doses did not (100, 101). In
keeping with these results, Qian et al. (79) found that LPS translocating from the intestine to the lungs reduced pulmonary epithelial cell TH2 responses to HDM, whereas translocating
dLPS enhanced allergen sensitivity (Fig. 4).
Taken together, the in vivo studies have shown that AOAH
may play important roles in terminating LPS- and Gram-negative bacteria-induced tolerance, restoring innate immune
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responsiveness, and influencing host susceptibility to pulmonary allergens.
An essential gene? Disease associations?
If AOAH is required to silence LPS in vivo in mice, does it
play a role in human disease causation? Although intronic
SNPs in the AOAH gene have been associated with chronic rhinosinusitis (102), asthma (103), and early onset Alzheimer’s disease (104), how these mutations might alter AOAH abundance
or function is not understood. Taking a different approach,
Gorelik et al. determined the three-dimensional structure of
AOAH, characterized its active site and catalytic mechanism,
and used this information to derive a list of mutations that
should alter the enzyme’s function (48). A comparison of this
list with the mutations listed in the human gnomAD browser
(Broad Institute, 2020) did not identify a homozygote (missense
or loss of function mutation) at any of the amino acid positions
predicted to alter the enzyme’s activity. This observation and
the gene’s conservation during evolution suggest that AOAH
might be an “essential” gene. Although an essential role has not
been apparent in AOAH-deficient C57Bl/6J or C3H/HeN laboratory mice, their ability to recover from natural infections and
many other challenges has not been tested.
It is also possible that AOAH production differs from individual to individual, and an interesting regulatory mechanism
has been suggested by human gene-disease association studies.
Several research groups have found highly significant associations between polymorphisms in the same intron in the HLADR region on chromosome 6 (6p21) and AOAH expression on
chromosome 7 (7p14.2). In one study, the polymorphism was
also associated with reduced risk of asthma (105), in another
study it was associated with lung cancer (106), and in several
other studies (107–109) a highly significant association was
found with colitis. The most detailed analysis was by Fairfax
et al. (109), who found that the minor C allele at an intronic
SNP (rs28366298) was specific to the HLA-DRB1*04, HLADRB1*07, and HLA-DRB1*09 alleles and that in each instance,
AOAH mRNA abundance in peripheral blood monocytes was
reduced and colitis risk was increased.
In both mice and humans, AOAH deficiency has been associated provisionally with less severe asthma and greater risk of
colonic inflammation. Discovering how AOAH expression on
chromosome 7 is regulated by an intronic sequence on chromosome 6 is a fascinating challenge. Studies to date have not
found evidence for regulation by cis-mediation, noncoding
RNA, or an intermediary gene product.
Conclusions
As Elsbach noted decades ago (7), “Effective host defense …
requires that the inflammation-generating foreign materials be
removed and the signals turned off.” We now know that many
host molecules can transiently inhibit LPSs without permanently silencing them, whereas AOAH irreversibly transforms
stimulatory LPS into a weak agonist that can competitively inhibit LPS signaling. Understanding how AOAH contributes to
silencing LPS and possibly other lipid-containing MAMPs
(such as bacterial outer membrane lipoprotein, a potent TLR2
agonist (48)) may yield insights applicable to MAMPs from
Figure 3. AOAH promotes recovery from tolerance. 1, LPS is injected into the peritoneal cavity of a naive Aoah1/1 or Aoah2/2 mouse. 2, the resident and
recruited peritoneal macrophages are stimulated by LPS and may internalize it. 3, after the initial inflammatory responses subside, the macrophages become
tolerant; bioactive LPS (orange stars) remains. 4, in the Aoah1/1 mouse, AOAH transforms LPS to dLPS (green stars), and the macrophages recover from tolerance. 5, if AOAH is absent, LPS cannot be inactivated (orange stars). Bioactive LPS in extracellular fluid keeps stimulating macrophages locally, preventing
them from recovering from tolerance. These mice are more likely to respond slowly and die quickly after they are challenged with live E. coli on day 10.
Figure 4. Intestinal AOAH modifies pulmonary immune responses. Colonic AOAH reduces translocation of bioactive LPS to the lungs, decreasing
induction of tolerance in pulmonary epithelial cells to Th2 allergens, such as
HDM.
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J. Biol. Chem. (2020) 295(51) 17842–17851 17847
other microbes, some of which may also require biochemical
modification for sustained inactivation (110, 111). Just as
“source control” (e.g. killing the bacteria, draining the abscess) is a critical step in managing infected patients who develop sepsis (112, 113), permanently silencing the patients’
inciting MAMPs may be needed to prevent prolonged infection sequelae (114) and coordinate with other resolving
mechanisms (1, 2) to clear the infection battlefield and
restore homeostasis.
Acknowledgments—We dedicate this review to Emil C. Gotschlich,
whose suggestion prompted the search for the LPS lipase; to Paul
D. Rick, whose Salmonella mutant enabled its discovery and assay;
and to the memory of Peter Elsbach (1924–2020), whose pioneering
studies on the mechanisms, regulation, and possible roles of bacterial digestion by host enzymes set the stage for the studies described
here. We also thank Wei Jiang and Luciana Giono for contributing
to the figures.
Funding and additional information—This work was supported by
National Natural Science Foundation of 论文帮助/论文写作服务/负担得起我及时提交我最好的质量 – China Grants 31570910,
31770993, and 91742104 (to M. L.) (Fudan), National Institutes of
Health Grants R01 AI18188 (to R. S. M.) and R01 AI059372 (to
J. P. W.), the Division of Intramural Research, NIAID, National
Institutes of Health (to R. S. M.), and Veterans Affairs Grant I01
BX000949/BX/BLRD (to J. P. W.). The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health.
Conflict of interest—The authors declare that they have no conflicts
of interest with the contents of this article.
Abbreviations—The abbreviations used are: MAMP, microbe-associated molecular pattern; LPS, lipopolysaccharide; AOAH, acyloxyacyl hydrolase; LBP, LPS-binding protein; sCD14, soluble CD14;
mCD14, membrane CD14; dLPS, AOAH-deacylated LPS; NK, natural killer; DC, dendritic cell; IL, interleukin; HDM, house dust
mite.
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