androgenetic alopecia (AGA) there is a prominent micro-inflammatory and fibrotic component.9,11 The observation that there are a plethora of mechanisms beyond androgens that contribute to hair loss lead many researchers to explore the role of inflammation and fibrosis in miniaturization of follicles,12,13 and to identify their part in the pathogenesis of, and impediment to successful treatment of hair loss.5Follicle immunology has thus become a topic of much hair research today as it is increasingly apparent that multiple immune driven pathways are involved in normal physiology of the follicle, as well as in the pathophysiology of hair loss when disrupted. Within the intrinsic follicular environment, multiple cytokines, growth and transcription factors signal the follicle to go into anagen vs. catagen phase and play a role in regeneration and renewal. In the event of micro-inflammation, overproduced cytokines like IL-1 and TNF-a are known to induce premature catagen, liberate ROS, cause apoptosis, and further propagate inflammation.5,9 Likewise, factors like TGF-b are prominently overproduced by the dermal papilla cells in the presence of androgens and signal growth arrest, as well as play a role in perifollicular fibrosis and miniaturization.14 These alterations in cytokine and protein expression – although not immediately destructive, over time chronically dysregulate physiological cycling dynamics and follicle stem cell homeostasis.3,5,9,15-17 To this end, any therapy designed to comprehensively treat hair loss must address not only triggering factors but also their downstream signaling cascades, as well as mitigate inflammation.Factors such as ultraviolet light, pollutants, toxins, stress, aging, smoking, antigenic exposure to bacteria, and fungi also generate ROS and promote a state of inflammation and oxidative stress in the follicle environment – contributing to hair loss.18,19 Recent research has additionally elucidated the molecular mechanisms underlying the role of psycho-emotional stress in causing and exacerbating hair loss. Sustained and chronic stress can lead to perifollicular inflammation and disruption of follicle physiology via endocrine and neuroimmune mediators like corticotropin releasing hormone (CRH), cortisol, and substance P (SP), all of which have receptors on the follicle.20,21,22As scientific research reveals more about hair follicle biology, we are compelled to look at the common thread within all hair disorders – the complex dysregulation of immune, inflammatory, and signaling cascades that regulate follicle homeostasis. Hence, any therapeutic that targets singular triggers such as androgens, without considering the pleiotropic downstream effects as well as the interplay of various signaling molecules, is destined to be incomplete. Further, the pathogenesis of hair loss is multi-factorial and requires a multi-modal solution that can additionally address factors like stress, aging, environment and inflammation. In consequence, an updated look on hair loss therapeutics emerges, one that does not focus on singular targets (monotargeting), but comprehensively addressesKoganthe multiple factors that affect the follicle, the downstream deregulated follicle immunology and signaling, as well as inflammation. A thorough look at hair physiology and the triggers that deregulate it follows below, supporting the need for a paradigm shift in hair loss treatment towards multi-targeting therapeutic strategies.The Regulation and Dysregulation of Hair Follicle Physiology – Consequences of Inflammation and Oxidative StressAll phases of the hair cycle are subject to intrinsic controls that induce either anagen (growth) or catagen (regression and apoptosis), followed by telogen (rest), ensuring that under normal conditions shedding is followed by new growth. As hair loss is ultimately the result of premature entry into the catagen phase, identifying which signals control this is vital for considering therapeutics.23 Growth in anagen is initiated by the dermal papilla cells (DPCs) which determine follicle and hair fiber characteristics, secrete mediators that regulate stem cells and influence growth of other follicular compartments.24 Although the intricate machinery of the follicle hasn’t been fully elucidated, a key signaling pathway regulating hair morphogenesis in anagen was identified to be the WNT pathway that mediates expression of a plethora of anagen-stimulating factors like IGF-1, bFGF, VEGF.25-28 Conversely, catagen is believed to occur as a result of both decreases in expression of anagen-maintaining factors, as well as increase in expression of pro-apoptotic cytokines like TGF-b, IL-1, TNF-a.29 Other controls intrinsically built into the follicle include its stem cell reservoirs and the hair follicle immune privilege (IP). The follicle being one of few sites in the body with IP, stresses the evolutionary importance of having it equipped with mechanisms for preventing the induction of both innate and adaptive immune responses. 30 The intrinsic mechanisms of the follicle are further subject to and integrated with signals from the macro-environment (eg, hormones, neurotransmitters) through endocrine, paracrine, and autocrine routes. As an example, androgens exert their effects via the DPCs, altering local immune balance by inducing DPC over-expression of catagen-promoting factors like TGF-b and other paracrine mediators that inhibit growth.14,31,32 Aside from androgens, hair follicles express receptors for estrogens, cortisol, retinoids, insulin, thyroid hormones, vitamin D, and many other known and unknown factors – the full influence of which is still being investigated, but points to the fact that these affect intrinsic signaling pathways and that a balance of all is what ultimately determines hair growth.14,31,32 Further, both follicles and other cells in the vicinity (eg, adipocytes, keratinocytes, fibroblasts, immune cells) also respond to systemic and environmental stimuli, generating mediators that shift local signaling, release ROS, and alter cycle control and growth.5,8,33 In hair loss, whether it is sudden (anagen or telogen effluvium) where alteration in the cycles of numerous follicles happens concurrently, creating sudden diffuse shedding, or asynchronous and
