Research Article
Gillian S. Ashcroft, Stuart J. Mills
Submitter: Michal Schwartz | michal.schwartz@weizmann.ac.il
Weizmann Institute of Science
Published November 22, 2002
In a recent article by Ashcroft and Mills in the Journal of Clinical Investigation it was asserted that testosterone has a negative effect on wound repair (1). The authors interpreted their findings to mean that the observed testosterone-induced interference with cutaneous wound healing is due to its proinflammatory effect. Their suggestion is based on the finding that at the sites of injury in male mice that were castrated or treated with an androgen-receptor inhibitor, fewer macrophages appeared and TNFa expression was weaker than at the sites of injury in intact or vehicle-treated male mice.
Significant sexual dimorphism has been demonstrated in wound repair and in the recovery of animal models from injury (2). Marked gender- related differences in mortality rates were also recently reported in patients with parasitic and infectious disease (3, 4). Similar findings to those of Ashcroft and Mills (1) were recently found by us in the injured spinal cord (5). In both models testosterone is suggested to have a negative effect on wound repair, although the proposed mechanisms underlying the effect are different. In both models, recovery in castrated males or in males treated with the androgen-receptor inhibitor Flutamide was better than in matched controls (1, 5). Sexual dimorphism was not observed in the recovery from spinal cord injury in mice lacking mature T cells (nude mice), in which recovery was also found to be significantly worse than in the wild-type. On the basis of these observations in the spinal cord injury model, we suggested that the observed gender-related differences in wound repair and recovery can be attributed to the testosterone-induced impairment of the systemic adaptive immune activity needed for wound repair rather than to its local proinflammatory effect. Our interpretation is supported by a large body of literature describing numerous in vitro and in vivo models in which testosterone was shown to inhibit T cell function (6-10). Testosterone ameliorates experimental autoimmune encephalomyelitis (EAE) through a direct effect on T lymphocytes (11-14). The suppressive effect of testosterone has also been described in the context of injury and wound repair: female mice with testosterone implants display significantly weaker cell-mediated immune responses in vivo than nonimplanted controls, and blockade of testosterone receptor restores cellular immunity in male mice (15-18).
Our group has shown that T cells mediate processes of tissue maintenance and wound repair in the injured CNS, and that they do this by regulating inflammatory processes at the injury site (19-23). Peterson et al. (1987) showed that T cell depletion significantly impairs wound healing (24, 25). It thus seems that lack of an appropriate systemic T cell response may result in a more vigorous innate response, with consequent hyperinflammation. Heavy macrophage invasion of the injury site might therefore result from a lack of T cell regulation.
The discrepancy between these two interpretations can be reconciled if local inflammation is viewed as a reflection of the severity of the wound and not as a player in the ongoing deterioration, unless its regulation by the systemic immune system is malfunctioning (for example, because of testosterone activity). Thus, the discrepancy in interpretation can be traced to differences in the way the innate immune response (often termed the inflammatory response) is perceived. Our view is that inflammation represents an attempt by the body to heal itself. When properly regulated by an adaptive systemic immune response, local innate inflammation has a favorable effect on wound repair. When T cell function is impaired, however, for example by testosterone, the result may be detrimental. It thus seems that the very factor that appears to give females an advantage over males in responding to an insult, namely the ability to sustain a cell-mediated autoimmune response (which in males is relatively suppressed), places them at a disadvantage with respect to autoimmune diseases (26), unless they are endowed with a naturally occurring immune regulatory mechanism, which renders them resistant to the development of autoimmune disease (27, 28).
References
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