Calcitonin gene-related peptide promotes reparative function of interleukin-4 educated human macrophages via COX1/PGD2 signalling

Interleukin-4 activated human macrophages (M(IL4) promote epithelial wound healing and exert an anti-colitic effect. Blood monocyte-derived M(IL4)s from healthy donors and individuals with Crohn’s disease had increased mRNA expression of the calcitonin gene-related peptide (CGRP) receptor chain, RAMP1, suggesting neural modulation of the M(IL4)s function. Thus, human (MIL4)s were treated with CGRP and the cells' phagocytic, epithelial wound repair and anti-colitic functions were assessed. M(IL4,CGRP)s had increased mannose receptor (CD206) and FcgRIIa (CD32a) mRNA expression, a subtle, but significant increase in phagocytosis, and decreased production of CXCL1, CCL3, CCL4, CCL5 and CXCL9 following exposure to E. coli. When delivered systemically (106 cells, ip.) to oxazolone-treated rag1-/- mice, M(IL4,CGRP) had an anti-colitic effect superior to M(IL4)s from the same healthy blood donor. The human colon CaCo2 epithelial cell line in an in vitro wounding model revealed that conditioned medium (CM) from M(IL4,CGRP) had increased amounts of TGFb and increased wound-healing capacity compared to matched M(IL4)-CM. Moreover, M(IL4,CGRP)s displayed increased cyclooxygenase (COX)-1 and prostaglandin D2, and CM from M(IL4,CGRP)s treated with indomethacin or SC-560 to inhibit COX1 activity failed to promote repair of wounded CaCo2 cell monolayers. These data confirm the human M(IL4)s’ anti-colitic effect that could be enhanced by the local availability of CGRP, which may be dependent, at least in part via macrophage COX1/PDG2 activity. Thus, neuronal input is revealed as an important local modifier capable of boosting the anti-colitic effect of autologous M(IL4) transfer to treat enteric inflammation