NK1 receptor mediates cerebral cellular and extracellular morphological changes during the LPS-induced febrile response

Abstract

Fever elicited by bacterial lypopolyssacharide (LPS) is mediated by pro-inflammatory cytokines, which activate central mediators and regulate the hypothalamic temperature setpoint. This response is often accompanied by morphological changes involving the extracellular matrix, neurons and glial cells, with significant health impacts. The NK1 receptor is involved in the febrile response induced by LPS but its effects over the extracellular matrix in the context of neuroinflammation remain unknown. The present work aims to clarify the extracellular changes associated with NK1 signaling in LPS-induced fever. Male Wistar rats were exposed to LPS intraperitoneally. Experimental groups were pre-treated intracerebroventricularly with the NK1 selective inhibitor SR140333B or saline. Histological changes involving the brain extracellular matrix were evaluated using hematoxylin and eosin, Mason’s trichrome, picrosirius, alcian blue, periodic acid Schiff’s stains. The expression of matrix metalloproteinase 9 (MMP9) was studied using confocal microscopy. Fever was accompanied by edema, perivascular lymphoplamacytic and neutrophylic infiltration, spongiosis and MMP9 overexpression. SR140333B significantly reduced LPS-induced fever (p < 0.0001), MMP9 overexpression (p < 0.01) and associated histological changes. These results contribute to characterize cerebral extracellular matrix changes associated with LPS-induced fever. Overall, the present work supports a role for NK1 receptor in these neuroinflammatory changes, involving MMP9 overexpression, edema and leukocytic infiltration.