Antimicrobial Peptides and Acne

15 May

Antimicrobial Peptides and  Acne
Michael P. Philpott

Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and the London, Queen Mary’s School of Medicine and Dentistry, University of London, London, U.K.

INTRODUCTION

It is well known that the epidermis forms  an effective structural barrier and  is also highly resistant to pathological infection by the many different types of microorgan- ism that  colonize  its surface.  If the epidermal barrier is  breached  by  pathogens, the  first  line  of defence  is the  hosts  innate immune  response  followed  by   the adaptive immune response. The innate immune response consists  of a number of pre-existing defence   mechanisms including  phagocytic and  natural killer  cells, mast cells as well as epithelial cells themselves (1). These cells respond to microbial pathogens in a number of ways  including the  release  of antimicrobial peptides. More  than   500  antimicrobial peptides  have   been  described in  plants,  insects, amphibians, and  mammals, with  broad-spectrum activity  against bacteria,  fungi, and viruses, representing an integral part of innate immunity (2,3). Of these antimi- crobial   peptides,  the   defensins,  adrenomedullin  (AM),   and   cathelicidins  are perhaps the  most  widely studied in  skin,  although to  date  only  defensins and AM appear to have  been investigated in acne.

DEFENSINS

Mammalian defensins are  a  family  of  cationic  antimicrobial peptides, 28 to  42 amino  acids  long,  containing three  disulfide bonds. They  have  been  divided into two  subtypes, the a-defensins and  the b-defensins (4). The a-defensins are found in  neutrophil granules [human neutrophil proteins (HNP)1 – 3] or  in  the  paneth cells  [human defensin (HD)5 – 6] of the  small  intestine (5). The  four  b-defensins so far  identified, human beta-defensin 1 to 4 (hBD1 – 4) are  produced in various epithelia including keratinocytes of the  epidermis (6,7). In keratinocytes, hBD1 is constitutive, whereas hBD2 – 4 are inducible and  are produced by keratinocytes in response to pro-inflammatory stimuli such  as interleukin 1 (IL-1), tumor necrosis factor (TNF), and  lipopolysaccharide (LPS).

The most  widely studied defensins in skin  are hBD1 and  hBD2 (8,9). Strong constitutive expression of both hBD1 and hBD2 mRNA  and protein can be detected in the distal  outer  root sheath (ORS) of the hair follicle, surrounding the hair canal and in the pilosebaceous duct (Fig. 1). It is of particular interest that hBD1 and hBD2 proteins appear to be strongly expressed in more suprabasal cells. These patterns of expression are consistent with  the concept that these regions are highly  exposed to microbial organisms, and  it is most  likely  that  hBD1 and  hBD2 play  a key role in protecting the pilosebaceous unit  from microbial invasion. In contrast, hair follicle compartments that  are rarely  exposed to microbial invasion such  as the proximal ORS and  inner  root  sheath (IRS) as  well  as  the  hair  follicle  bulb,  including the

FIGURE 1    (See color insert.) Human  beta-defensin 1 (hBD1) and hBD2 immunoreactivity in human hair  follicles. hBD1  (A) and  hBD2  (B)  immunoreactivity is found  in the  suprabasal layers of the epidermis and  the distal outer  root sheath (ORS)  of the hair follicle. Strong  basal expression is seen in  the   bulge  area,  which  contains  a   population  of  epidermal  stem   cells.  Strong   b-defensin expression is also  found  in the  sebaceous gland and  duct.  Weaker expression is present in the suprabasal layers of the central  and  proximal ORS  and  in the proximal inner root sheath. hBD1 and hBD2 IR are  not detected in the  hair matrix or the  dermal papilla. Abbreviations: APM, arrector pili muscle; DP, dermal papilla; IRS, inner root sheath; ORS,  outer root sheath. Source: From Ref. 9.

dermal papilla (DP), showed only  very  weak  hBD1 and  hBD2 expression. More- over,  as  we  shall  discuss below  it  would also  appear that  as  well  as  defensin expression in  compartments  with   high  exposure to  microorganisms, defensins are also expressed in potential hair  follicle stem  cell compartments.

Perhaps, one  of  the  most   striking  observations  with   regard  to  defensin expression in normal skin  is that  in contrast to the hair  canal,  pilosebaceous duct and  interfollicular epithelium (8,9), where defensin expression is restricted to the cells  of the  suprabasal layers.  In  the  central   ORS and  the  buzlge region  of the hair  follicle, strong  defensin expression is found in basal  keratinocytes. This may be very  important as it is accepted the  central  ORS and  bulge  of the  hair  follicle contain a population of epidermal stem  cells (10 – 12). It is therefore tempting to speculate that  the role of b-defensins in this  region  of the ORS may  be to protect stem  cells from  microbial invasion. A similar role for defensins has  recently been proposed  in  the  gut,   where  marked  defensins  expression is  detected  in  the paneth cells of the small intestine (2). Since paneth cells are located  in the intestinal crypts,  it has  been  suggested that  paneth cell secretions might  protect stem  cells from pathogenic microbes. Whether defensins play an important role in protecting stem  cells in the hair follicle remains to be investigated. However, it is also of note that the distal  hair follicle containing the DP and  hair follicle matrix  are very weak expressers  of  defensins.  The  lower   hair   follicle  is  transient  and   during  the hair  growth cycle  undergoes  apoptotic driven  regression (11,13,14).  Moreover, if surgically removed, the  lower  follicle including the  DP and  matrix  are  able  to regenerate  (15,16).  Therefore,  lack   of  or   weak   defensin  expression  in   these regions may  reflect  the  transient nature of this  part  of the  hair  follicle,  and  the fact  that  if  lost  through  mechanical injury   and   presumably  infection they  can regenerate. Whereas, the proximal hair follicle including the stem cell compartment cannot  regenerate and  must  therefore be protected.

ADRENOMEDULLIN

AM  is a 52-amino  acid  ringed structure peptide with  C-terminal amidation that mediates vasodilatory and  natriuretic properties through the  second messenger cAMP, nitric oxide, and  the renal  prostaglandin system. In addition to these  cardi- ovascular and renal effects, AM is involved in a remarkable range  of other functions involving growth regulation, modulation of hormone secretion, neurotransmission, and  antimicrobial defence  (17). AM is synthesized as part  of the larger  precursor molecule preproAM,  which   contains  an  additional  biologically active   peptide termed  preproAM  N-terminal  20  peptide  or  PAMP   (18).  The  effects  of  AM appear to  be  mediated by  two  different receptors: L1,  a  previously identified orphan  receptor and   calcitonin receptor like  receptor (CRLR)  which   can  bind either   calcitonin gene  related peptide or  AM,  depending on  whether receptor activity  modifying proteins are co-associated with  CRLR (19,20).

In normal human skin, AM is expressed in suprabasal layers of the epidermis, in  melanocytes, and  in  sweat   and  sebaceous glands (8,21). In  the  hair  follicle, AM protein is expressed in the  basal  and  suprabasal layers  of the  hair  bulb  and the  proximal ORS. Whereas, in the  distal  ORS AM  becomes increasingly supra- basal,  especially in  proximity to  the  bulge  region.  In  contrast to  defensins, AM immunoreactivity (IR) is absent from  the  basal  cells  of the  bulge.  The  CRLR is expressed in  a similar pattern to  that  of AM.  In  contrast, the  L1 IR receptor is only expressed in suprabasal cells (21).

AM has  antimicrobial effects against both  Gram-positive and  -negative bac- teria  isolated from  the  skin  and  oral  cavity.  Moreover, antimicrobial activity  is most marked for Propionibacterium acnes and Micrococcus luteus with minimal inhibi- tory  concentrations close to AM concentrations measured in sweat  (22). AM also acts  as  an  autocrine/paracrine growth factor  in  different tumor cell  lines  (23), Swiss  3T3 fibroblasts (24), vascular smooth muscle  cells (25), as well  as keratino- cytes  of skin  (26), and  oral  mucosa (27). Based  on  these  data,  possible roles  for AM in the innate unspecific immune system of the skin and a possible participation of AM in the regulation of skin proliferation, wound repair, hair growth, and tumor progression have  been postulated.

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