An investigation into sex-differences into sex-differences in leukocyte mobilisation and recruitment in response to acute inflammation

Abstract

Females are relatively protected from inflammatory diseases, particularly conditions that are characterised by excessive tissue infiltration of neutrophils (PMNs), such as ischaemia/reperfusion (I/R) injury. Therefore, understanding sex-differences is very important particularly for appropriate treatment of inflammatory disorders in men and women. Unfortunately, efforts to exploit sex-differences therapeutically have been unsuccessful since the precise mechanisms that confer the protective advantage in females over males are unclear. Many fundamental aspects ofthe nature of sex-differences have not been investigated, particularly in the regulation of PMN mobilisation from the bone marrow during acute inflammation. The aim ofthis thesis is to determine the nature and mechanism of leukocyte activation and recruitment in males and females, particularly in I/R. This thesis demonstrates for the first time that regulation of PMN mobilisation during acute inflammation is distinct in females. In comparison to males, females demonstrate reduced expression of mediators that cause the release of PMNs, including GCSF, CXCR2 and CXCLS, and increased expression of CXCR4 and CXCl12, which mediate PMN retention in the bone marrow. Reduced granulopoiesis, PMN mobilisation and recruitment into tissues in response to inflammogens protect females from collateral damage incurred by PMN-derived mediators that contribute to tissue injury and loss of function. This thesis has also revealed a novel, and possibly predominant, role for the ElR+ CXC chemokine CXClS in mobilisation of tissue-damaging PMNs from the bone marrow, whereby CXCLS production, PMN mobilisation and tissue infiltration was profoundly greater in males during acute inflammation. CXClS appears to stimulate PMN mobilisation by 1) upregulating CXCR2 iv / expression on bone marrow cells and simultaneously downregulating CXCR4 expression; 2) inducing its own expression; 3) stimulating GCSF expression; and 4) increasing PMN expression of J32 integrin. Thus, the thesis proposes that reduced CXCLS expression, and increased CXCR4/CXCL12 expression, in females during acute inflammation may be a novel mechanism underlying the protection against tissue injury. The fact that these sex- differences were apparent in different species (rat, mouse), tissues (mesenteric, lung, kidney, heart), in response to different stimuli (mesenteric, renal, myocardial I/R and carrageenan-induced pleurisy) and shown both in vivo and in vitro, suggests that this is a fundamental, and more generalised, phenomenon in males and females following acute inflammation. The inherent differences between the sexes have important clinical implications in that they demonstrate the need of considering sex-differences in research. This thesis demonstrates that sex-differences must be taken into account when developing such therapies for specific inflammatory diseases such as I/R injury as there are major differences in the temporal profile of chemokines and the extent of PMN infiltration.EThOS - Electronic Theses Online ServiceGBUnited Kingdo