Estrogens as regulator of hematopoietic stem cell, immune cells and bone biology.

Hematopoietic stem cells provide continuous supply of all the immune cells, through proliferation and differentiation decisions. These decisions are controlled by local bone marrow environment as well as by long-range signals for example endocrine system. Sex dependent differential immunological responses have been described under homeostasis and disease conditions. Females show higher longevity than male counterpart that seems to depend on major female sex hormone, estrogen. There are four estrogens - Estrone (E1), estradiol (E2), Estriol (E3) and Estetrol (E4) that spatially and temporarily present during different female reproductive phases. In this review, we discussed recent updates describing the effects of estrogen on HSC, immune cells and in bone biology. Estradiol (E2) being a major/abundant estrogen is extensively investigated, while effects of other estrogens E1, E3 and E4 are started to unravel recently. Furthermore, clinical effect of estrogen as hormone therapy is discussed in HSC and immune cells perspectives. The data presented in this review is compiled by searches of PubMed, database of American Cancer Society (ACS). We have included article from September 1994 to March 2020 as covering all article in chronological order is not fissile so we included relevant article with substantial information in this specific area of research by using the search term (alone or in combination) estrogen, hematopoietic stem cell, immune cells, gender difference, estrone, estriol, estetrol, therapeutic application, pregnancy, effect on bone.

The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation.

Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.