Opposite effects of substance P and calcitonin gene-related peptide in oxazolone colitis

Background

Extrinsic sensory neurons play a crucial role in aberrant immune responses in colitis. The activation of peptidergic sensory nerve fibres is accompanied by a release of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). SP levels increase whilst CGRP levels decrease in colon specimens from patients with inflammatory bowel disease; thus suggesting the pro- and anti-inflammatory roles, respectively, of these neuropeptides.

Methods

Oxazolone (4-ethoxymethylene-2-phenyl-2-oxazolin-5-one) colitis was induced in wild-type (WT), SP and CGRP knockout (^−/−) mice. CGRP^−/− mice were treated with the neurokinin 1-receptor antagonist CP-96345 (CP). The permeability of the mouse colon was evaluated by Evans Blue uptake. Cytokines produced by colonic lamina propria mononuclear cells were measured by ELISA.

Results

Colons of WT, CGRP^−/− and SP^−/− mice showed similar tissue architecture and permeability. SP^−/− mice were protected against oxazolone colitis, whereas CGRP^−/− showed increased susceptibility to colitis compared to WT mice. SP^−/− and CP-treated CGRP^−/− mice showed no significant body weight loss during the period of sickness in contrast to untreated CGRP^−/− and WT mice. Decreased production of IL-4, IL-5, and IL-13 by colonic lamina propria mononuclear cells of the protected SP^−/− mice confirms the crucial role of these cytokines in oxazolone colitis.

Conclusion

We demonstrate that the neuropeptides CGRP and SP exert opposing effects in oxazolone colitis and provide further evidence for a prominent neuroimmune association in the gut.     

Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke

Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRβ)⁺ and CD105⁺ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRβ⁺ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.