Inflammatory Monocytes and Subsets of Macrophages with Distinct Surface Phenotype Correlate with Specific Integrin Expression Profile during Murine Sepsis

Abstract

Monocytes and macrophages participate in both pro- and anti-inflammatory responses during sepsis. Integrins are the cell adhesion receptors that mediate leukocyte migration and functions. To date, it is not known whether integrin profiles correlate with their trafficking, differentiation, and polarization during sepsis. In this study, using endotoxemia and cecal ligation and puncture model of murine sepsis, we have analyzed the role of surface integrins in tissue-specific infiltration, distribution of monocytes and macrophages, and their association with inflammation-induced phenotypic and functional alterations postinduction (p.i.) of sepsis. Our data show that Ly-6C^hi inflammatory monocytes infiltrated into the peritoneum from blood and bone marrow within a few hours p.i. of sepsis, with differential distribution of small (Ly-6C^loCD11b^loF4/80^lo) and large peritoneal macrophages (Ly-6C^loCD11b^hiF4/80^hi) in both models. The results from flow cytometry studies demonstrated a higher expression of integrin α₄β₁ on the Ly-6C^hi monocytes in different tissues, whereas macrophages in the peritoneum and lungs expressed higher levels of integrin α₅β₁ and α_vβ₃ in both models. Additionally, F4/80⁺ cells with CD206^hiMHCII^lo phenotype increased in the lungs of both models by six hours p.i. and expressed higher levels of integrin α_vβ₃ in both lungs and peritoneum. The presence of such cells correlated with higher levels of IL-10 and lower levels of IL-6 and IL-1β transcripts within six hours p.i. in the lungs compared with the mesentery. Furthermore, bioinformatic analysis with its experimental validation revealed an association of integrin α₄ and α₅ with inflammatory (e.g., p-SRC) and integrin α_v with regulatory molecules (e.g., TGFBR1) in macrophages during sepsis.