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Transcriptome profiles of pancreatic macrophage following AP injury

ABSTRACT: Upon injury, immune cells undergo dynamic changes in population size, differentiation state and function in response to maintain organismal integrity. Myeloid cells, mostly macrophages have been shown to act as positive regulators of development, tissue homoeostasis, inflammation，especially in inducing resolution after inflammation, remodeling and repair. Here we report what specific role macrophages play in every precisely dynamical period after injury in vivo. We first confirmed that M2-like macrophages from recruited monocytes accumulate during AP recovery(RAP). By macrophage depletion in different time points, before or after ADM phase, we elucidate distinct roles of macrophage in different stages of AP recovery. To further understanding the phenotype and function of macrophage during AP recovery, pancreatic macrophages were isolated in all precisely indicated time points for RNA-seq analysis. By analyzing RNA-seq result, we verify PI3K-AKT activation in macrophage aids in resolving inflammation in ADM phase and IL4RA deficiency impairs M2-like macrophages and AP recovery. Finally, we further investigated PGE2’s role in regulating M2 macrophage polarization and we found PGE2 augments IL4Ra signaling to enhance M2 activation of macrophage.

ORGANISM(S): Mus musculus

PROVIDER: GSE138134 | GEO | 2020/08/10

REPOSITORIES: GEO

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Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

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Transcriptome profiles of pancreatic macrophage following AP injury

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