Androgen Receptor Influences on Body Defense System via Modulation of Innate and Adaptive Immune Systems: Lessons from Conditional AR Knockout Mice

Upon insult, such as infection or tissue injury, the innate and adaptive immune systems initiate a series of responses to defend the body. Recent studies from immune cell-specific androgen receptor (AR) knockout mice demonstrated that androgen and its receptor (androgen/AR) play significant roles in both immune regulations. In the innate immunity, androgen/AR is required for generation and proper function of neutrophils; androgen/AR also regulates wound healing processes through macrophage recruitment and proinflammatory cytokine production. In adaptive immunity, androgen/AR exerts suppressive effects on development and activation of T and B cells. Removal of such suppression causes thymic enlargement and excessive export of immature B cells. Altogether, androgen/AR plays distinct roles in individual immune cells, and targeting androgen/AR may help in treatment and management of immune-related diseases.The immune system includes both innate and adaptive immune responses. Once insult to the body (eg, infection) is initially encountered, the innate system acts within minutes, followed some hours later by early induced responses conducted by recruited effector cells, such as neutrophils and macrophages, in a nonspecific manner.^1,2 In most cases, infections are eliminated by the innate immune system. When pathogens breach the first line of immune defense, however, the adaptive immune system is activated with antigen-specific effectors (eg, T and B cells), and the generation of memory cells ensures a long-lasting and prompt response to recurrent infection with the same pathogens. On the other hand, the context of the activated innate immunity also shapes the outcome of adaptive immune responses.³Androgen and androgen receptor (AR) signals control the development and function of both male and female reproductive systems.^4–6 The AR gene is located on the X chromosome in both the human and the murine genome. AR is a prototypical nuclear receptor, containing an N-terminal domain, a ligand-binding domain, a DNA-binding domain, and a C-terminal domain.⁷ After binding of its ligands, testosterone or 5α-dihydrotestosterone, AR translocates into the nucleus and binds to androgen responsive elements on the promoters or enhancers of target genes, thereby turning on their expression.⁸ The expression of AR has been detected in various immune cell lineages, including neutrophils, mast cells, macrophages, B cells, and T cells,^9–11 implying the involvement of androgen and its receptor (androgen/AR) in regulating the development and function of the immune system.It has long been suspected that, in both animals and humans, the male sex hormones may modulate the development and function of the immune system. Males are at higher risk of developing sepsis, acute respiratory distress, and multiorgan failure after soft-tissue traumatic hemorrhagic shock and thermal injury, in part because of immune suppression and abnormal activation of neutrophils.¹² On the other hand, males are less prone to autoimmune diseases. Of more than 70 chronic disorders categorized as autoimmune diseases, many affect predominantly women.^13,14 Various studies have uncovered important immune regulatory functions of androgen/AR (as discussed below), and such nonclassical roles of androgen/AR outside the reproductive system are important for understanding the pathogenesis of these immunological conditions.Recent studies using conditional AR knockout (ARKO) mice, with knockout of AR in selective immune cells, opened a new era for investigating the nonclassical roles of androgen/AR involved in immune regulation; these studies also suggest potential for the development of new therapeutic strategies for treating immune-related diseases.^6,15 In this review, we summarize the roles of androgen/AR in both the innate and adaptive components of the immune system (specifically neutrophils, macrophages, T cells, and B cells), as well as new evidence from studies using conditional ARKO mice. We also address the potential influences of androgen/AR on immune-related diseases.