Extracellular CIRP Induces Inflammation in Alveolar Type II Cells via TREM-1

Abstract

Extracellular cold-inducible RNA-binding protein (eCIRP) induces acute lung injury (ALI) in sepsis. Triggering receptor expressed on myeloid cells-1 (TREM-1) serves as a receptor for eCIRP to induce inflammation in macrophages and neutrophils. The effect of eCIRP on alveolar epithelial cells (AECs) remains unknown. We hypothesize that eCIRP induces inflammation in AECs through TREM-1. AECs were isolated from C57BL/6 mice and freshly isolated AECs were characterized as alveolar type II (ATII) cells by staining AECs with EpCAM, surfactant protein-C (SP-C), and T1 alpha (T1α) antibodies. AECs were stimulated with recombinant murine (rm) CIRP and assessed for TREM-1 by flow cytometry. ATII cells from WT and TREM-1 –/– mice were stimulated with rmCIRP and assessed for interleukin-6 (IL-6) and chemokine (C-X-C motif) ligand 2 (CXCL2) in the culture supernatants. ATII cells from WT mice were pretreated with vehicle (PBS), M3 (TREM-1 antagonist), and LP17 (TREM-1 antagonist) and then after stimulating the cells with rmCIRP, IL-6 and CXCL2 levels in the culture supernatants were assessed. All of the freshly isolated AECs were ATII cells as they expressed EpCAM and SP-C, but not T1α (ATI cells marker). Treatment of ATII cells with rmCIRP significantly increased TREM-1 expression by 56% compared to PBS-treated ATII cells. Stimulation of WT ATII cells with rmCIRP increased IL-6 and CXCL2 expression, while the expression of IL-6 and CXCL2 in TREM-1 –/– ATII cells were reduced by 14 and 23%, respectively. Pretreatment of ATII cells with M3 and LP17 significantly decreased the expression of IL-6 by 30 and 47%, respectively, and CXCL2 by 27 and 34%, respectively, compared to vehicle treated ATII cells after stimulation with rmCIRP. Thus, eCIRP induces inflammation in ATII cells via TREM-1 which implicates a novel pathophysiology of eCIRP-induced ALI and directs a possible therapeutic approach targeting eCIRP-TREM-1 interaction to attenuate ALI.

Normothermic machine perfusion attenuates hepatic ischaemia‐reperfusion injury by inhibiting CIRP‐mediated oxidative stress and mitochondrial fission

“… 4 , 5 Recently, growing evidence shows that extracellular CIRP can function as a novel damage‐associated molecular pattern (DAMP) molecule that triggers proinflammatory responses. 6 , 7 , 8 In addition, blocking CIRP protein significantly increases the survival rate in a mouse hepatic ischaemia‐reperfusion model. 9 The DCD liver experiences hypotension before donation and suffers from hypothermia and hypoxia during cold storage (CS).…”

Clinical relevance for circulating cold-inducible RNA-binding protein (CIRP) in patients with adult-onset Still’s disease

“…iCIRP has its role in regulating cellular stress responses, such as mRNA stability, cell proliferation cell survival, and tumor formation [ 21 ]. In contrast to iCIRP, eCIRP is presumed to function as a DAMP-enhancing inflammation and tissue injury [ 22 ]. eCIRP was able to induce proinflammatory cytokines through activating innate immune cells [ 9 ].…”

The role of Cold‐Inducible RNA‐binding protein in respiratory diseases

“…AECs are an important part of the alveolar‐capillary barrier, which helps with gas exchange and protects the lung from pathogens. A recent study showed that in isolated primary AECs, mostly AEC type II (ATII) cells, treatment with rmCIRP could significantly induce cytokine IL‐6 and chemokine CXCL2 production in a dose‐dependent manner, indicating that eCIRP could induce a pro‐inflammatory phenotype in ATII cells 29 . As the migration of neutrophils requires the binding of chemokines to chemokine receptors.…”