The Contribution of Chemoattractant GPCRs, Formylpeptide Receptors, to Inflammation and Cancer

Abstract

A hallmark of inflammatory responses is leukocyte mobilization, which is mediated by pathogen and host released chemotactic factors that activate Gi-protein-coupled seven-transmembrane receptors (GPCRs) on host cell surface. Formylpeptide receptors (FPRs, Fprs in mice) are members of the chemoattractant GPCR family, shown to be critical in myeloid cell trafficking during infection, inflammation, immune responses, and cancer progression. Accumulating evidence demonstrates that both human FPRs and murine Fprs are involved in a number of patho-physiological processes because of their expression on a wide variety of cell types in addition to myeloid cells. The unique capacity of FPRs (Fprs) to interact with numerous structurally unrelated chemotactic ligands enables these receptors to participate in orchestrated disease initiation, progression, and resolution. One murine Fpr member, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), have been demonstrated as key mediators of colon mucosal homeostasis and protection from inflammation and associated tumorigenesis. Recent availability of genetically engineered mouse models greatly expanded the understanding of the role of FPRs (Fprs) in pathophysiology that places these molecules in the list of potential targets for therapeutic intervention of diseases.

FAM3D is essential for colon homeostasis and host defense against inflammation associated carcinogenesis

“…There were similarities in the phenotype among Fam3D −/− , Fpr2 −/− , and Fpr1/2 −/− mice, and mice deficient in another Fpr2 agonist Cramp in that they all showed increased susceptibility to chemically induced colitis. FPRs (mouse Fprs) are members of G protein-coupled chemoattractant receptors with 7transmembrane structure and were originally identified as regulators of the recruitment of phagocytic leukocytes and activation of microbicidal respiratory burst 28 . It has been shown that Fpr2 recognizes a variety of pathogen and host-derived chemotactic agonists 29 .…”

The G‐protein‐coupled chemoattractant receptor Fpr2 exacerbates neuroglial dysfunction and angiogenesis in diabetic retinopathy

“…48,49 CRAMP controls normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. 50 CRAMP also directly activates vascular endothelial cells to promote cell proliferation and form vascular-like structures. 51 Likewise, human LL-37 promotes the proliferation and tubule form of umbilical vein endothelial cells through FPR2.…”

“…The mouse homolog of LL37 is CRAMP, an important effector molecule of the innate immune system that induces leukocyte chemotaxis and activation 48,49 . CRAMP controls normal mouse colon epithelial growth, repair and protection against inflammation‐associated tumorigenesis 50 . CRAMP also directly activates vascular endothelial cells to promote cell proliferation and form vascular‐like structures 51 .…”

Genomic profiling of cancerous patients identifies FPR2 as an alternative immunotherapeutic target in glioblastoma multiforme

“…The results were screened by the criteria: |logFC| > 2, FDR<0.05. Among these DEGs, we selected 6 hub genes (FPR2, VEGFA, SERPINA1, SOX2, PBK, ITGB3) with a higher degree of connectivity and could be a potential biomarker for GBM prognosis [20,27,47,49]. The considerably different expression level of FPR2 was presented in violin plots and box plots.…”