Resolution of acute inflammation was long assumed to return tissue to its pre-inflammatory state, but work in the zymosan peritonitis model showed that resolving (but not hyperinflammatory) insults trigger a third, post-resolution phase: a weeks-to-months-long infiltration of tissue-resident macrophages, Ly6C^hi monocyte-derived macrophages, monocyte-derived dendritic cells, and myeloid-derived suppressor cells, alongside lymph-node expansion, regulatory T-cell induction, and a paradoxical, prolonged immune-suppressed state. Later work by the same group identified one causative pathway — an NK-cell IFNγ trigger driving sustained macrophage COX-1/mPGES-1-derived prostaglandin E2 that suppresses lymphocyte function — validated in mice and humans. What remains open is the complete causal account of the post-resolution phase: how efferocytosis-linked events connect to iNOS expression, regulatory T-cell induction, and months-long durable tolerance; whether post-resolution Ly6C^hi effector monocytes promote adaptive immunity from within the inflamed tissue or directly from blood to lymph nodes; and the molecular reprogramming underlying 'adapted homeostasis', the altered tissue state that dictates future inflammatory responses.

Background

Acute inflammation proceeds in classically defined phases: an onset phase dominated by polymorphonuclear neutrophils (PMNs, the granulocytic white cells that arrive first at a site of injury or infection), followed by a resolution phase in which mononuclear phagocytes clear the stimulus and dead cells. A central process of resolution is efferocytosis — the phagocytic clearance of apoptotic (deliberately self-destructing) cells, principally spent neutrophils — which typically reprograms the engulfing macrophage toward anti-inflammatory and tissue-repair behavior. It was long assumed that successful resolution returns the tissue to its pre-inflammatory state. The model system here is murine peritonitis induced by low-dose zymosan (a fungal cell-wall component that triggers a self-limited inflammatory reaction), in which the University College London group of Gilroy and colleagues discovered a previously overlooked third, post-resolution phase. After resolution of low-dose zymosan (or bacterial) peritonitis, tissues remain populated for weeks to months by four mononuclear phagocyte populations: tissue-resident macrophages (resMφs, embryonically derived, self-maintaining macrophages that repopulate the cavity), Ly6C^hi monocyte-derived macrophages (moMφs; Ly6C^hi denotes the inflammatory, CCR2-dependent monocyte subset that gives rise to them), monocyte-derived dendritic cells (moDCs, antigen-presenting cells derived from the same monocytes), and myeloid-derived suppressor cells (MDSCs, immature myeloid cells capable of suppressing T-cell responses). This post-resolution phase features lymph-node expansion followed by contraction, induction of FoxP3-expressing CD4 regulatory T cells (Tregs, the suppressive T-cell lineage), and a prolonged state of local immune suppression. The original paper (Newson et al., Blood 2014) further showed that efferocytosing resMφs migrate to draining lymph nodes and drive lymph-node contraction in an inducible nitric oxide synthase (iNOS, the enzyme producing the immunosuppressive free radical nitric oxide)-dependent manner, that post-resolution moMφs persist for months and dictate the magnitude of secondary inflammatory reactions, and that hyperinflammatory stimuli (high-dose zymosan) fail to induce this program. The authors termed the altered post-resolution tissue state 'adapted homeostasis' (also written 'adaptive homeostasis') and posed these open questions: why a neutrophil-driven acute onset is paradoxically accompanied by months-long immune suppression and through which molecular triggers and signaling pathways; whether the CCR2-expressing Ly6C^hi effector monocytes amplify adaptive immunity only after entering the peritoneal cavity or also directly from blood to lymph nodes; and what the molecular basis of adapted homeostasis is. Substantial progress followed. Newson et al. (Cell Reports 2017), in the same peritonitis model, established a first causal pathway: at resolution, infiltrating natural killer (NK) cells secrete interferon-γ (IFNγ), which via CXCL10 chemokine signaling drives monocyte recruitment and upregulates cyclooxygenase-1 (COX-1) and microsomal prostaglandin E synthase-1 (mPGES-1) in macrophages, sustaining biosynthesis of prostaglandin E2 (PGE2, a lipid mediator that acts through G-protein-coupled EP receptors, notably EP4). This PGE2 program suppresses lymphocyte function, generates MDSCs, impairs antigen uptake and presentation, creates a window of susceptibility to secondary bacterial infection, and prevents formation of anti-dsDNA autoantibodies (antibodies against double-stranded DNA, a serological hallmark of lupus-like autoimmunity) in the dysregulated high-dose model — an evolutionary trade-off between infection risk and autoimmunity. Motwani et al. (PLoS One 2017) confirmed the phenomenon in humans using intradermal UV-killed Escherichia coli: post-resolution sites accumulate memory T cells and CD163+ macrophages (CD163 is a hemoglobin–haptoglobin scavenger receptor used as a marker of resident-type, alternatively activated macrophages) for at least 17 days, with tissue memory CD4 cells under endogenous PGE2–EP4 control. Fonseca et al. (Cell 2015) showed a pathological counterpart after Yersinia infection, in which microbiota-dependent tissue remodeling persistently diverts dendritic cells and compromises mucosal tolerance. Feehan and Gilroy (Trends in Molecular Medicine 2019) codified 'adapted homeostasis' as a concept; Feehan et al. (Nature Communications 2024) extended the framework to pneumococcal pneumonia, showing that monocyte-derived post-resolution macrophages, transcriptomically enriched in prostaglandin-biosynthesis and T-cell-differentiation genes, maintain lung tissue-resident CD4 memory and limit fibrosis via PGE2–EP4 signaling for up to six weeks. Related work has shown that aging impairs the efferocytosis entry point of this cascade through elevated signaling by p38 MAP kinase (p38 mitogen-activated protein kinase, a stress-activated intracellular signaling enzyme) (De Maeyer et al., Nature Immunology 2020), and that epoxy-oxylipin lipid mediators (fatty-acid epoxides produced by cytochrome P450 enzymes that act as signaling lipids) direct human monocyte fate during resolution (Bracken et al., Nature Communications 2026). Despite this progress, the field's mechanistic account remains centered on a single prostaglandin axis, and several of the original questions — notably the complete efferocytosis-to-durable-tolerance causal chain, the monocyte trafficking route, and the molecular basis of adapted homeostasis — lack dedicated closure in the literature.

Problem Statement

The task is to causally dissect the post-resolution phase of acute inflammation: identify and experimentally validate the cellular and molecular mechanisms by which a successfully resolving inflammatory reaction (as in low-dose zymosan or bacterial peritonitis) establishes a prolonged, systemic and local state of immune suppression and tissue reprogramming lasting weeks to months, instead of returning the tissue to its pre-inflammatory state. Concretely, an answer must account for: (i) the complete causal chain linking efferocytosis of apoptotic neutrophils by tissue-resident macrophages — beyond the already-established NK-cell IFNγ to macrophage COX-1/mPGES-1 to PGE2 axis — to iNOS expression, regulatory T-cell induction, and the maintenance of durable immunological tolerance over months, including why this state follows resolving but not hyperinflammatory stimuli; (ii) whether post-resolution CCR2-expressing Ly6C^hi effector monocytes amplify adaptive immunity only after migrating into the inflamed tissue/cavity or also directly from the blood into draining lymph nodes; and (iii) the molecular reprogramming of tissue-resident and monocyte-derived macrophages that constitutes 'adapted homeostasis', and how that reprogramming causally dictates the magnitude and character of subsequent inflammatory and adaptive immune responses. These three questions are scientifically linked components of one objective — a validated mechanistic account of the post-resolution phase.

References

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