Review article Critical role of mast cells in inflammatory diseases and the effect of acute stress Theoharis C. Theoharides a,b,c, * , David E. Cochrane d a Department of Pharmacology and Experimental Therapeutics, Tufts-New England Medical Center, Boston, MA, USA b Department of Biochemistry, Tufts-New England Medical Center, Boston, MA, USA c Department of Internal Medicine, Tufts-New England Medical Center, Boston, MA, USA d Department of Biology, Tufts University, Medford, MA, USA Received 2 July 2003; received in revised form 15 October 2003; accepted 16 October 2003 Abstract Mast cells are not only necessary for allergic reactions, but recent findings indicate that they are also involved in a variety of neuroinflammatory diseases, especially those worsened by stress. In these cases, mast cells appear to be activated through their Fc receptors by immunoglobulins other than IgE, as well as by anaphylatoxins, neuropeptides and cytokines to secrete mediators selectively without overt degranulation. These facts can help us better understand a variety of sterile inflammatory conditions, such as multiple sclerosis (MS), migraines, inflammatory arthritis, atopic dermatitis, coronary inflammation, interstitial cystitis and irritable bowel syndrome, in which mast cells are activated without allergic degranulation. D 2003 Elsevier B.V. All rights reserved. Keywords: Inflammation; Mast cells; Stress; Vascular permeability 1. Selective release of mast cell mediators Mast cells derive from a distinct precursor in the bone marrow (Rodewald et al., 1996) and mature under local tissue microenvironmental factors (Galli, 1993). Mast cells are necessary for the development of allergic reactions, through crosslinking of their surface receptors for IgE (FcqRI), leading to degranulation and the release of vaso- active, pro-inflammatory and nociceptive mediators that include histamine, cytokines and proteolytic enzymes (Kobayashi et al., 2000; Galli et al., 2002). The multitude of mediators that could be secreted has given rise to new speculations about the possible role of mast cells in immune responses (Gurish and Austen, 2001), whether it is acquired immunity (Marone et al., 2002) or in response to bacteria (Malaviya and Abraham, 2001). As the spectrum of diseases that may involve mast cells increases, so do the questions concerning the triggers and the mechanisms through which mast cells may be able to participate in such diverse conditions without the ‘‘classic’’ degranulation by exocyto- sis typical of anaphylactic reactions. A main aspect of mast cell physiology that had been largely ignored until recently is that mast cells can secrete mediators without overt degranulation (Theoharides and Douglas, 1978), through differential or selective release (Theoharides et al., 1982), this process is probably regulated by the action of distinct protein kinases on a unique phos- phoprotein (Theoharides et al., 1980; Sieghart et al., 1978). Unlike allergic reactions, mast cells are rarely seen to degranulate during autoimmune (Benoist and Mathis, 2002) or inflammatory processes (Woolley, 2003); moreover, the ‘‘mast cell stabilizer’’ disodium cromoglycate (cromolyn) may be ineffective as a therapeutic modality (Okayama et al., 1992). Instead, mast cells appear to undergo ultrastruc- tural alterations of their electron dense granular core indi- cative of secretion, but without overt degranulation, a process that has been termed ‘‘activation’’ (Dimitriadou et al., 1990; Dimitriadou et al., 1991; Theoharides et al., 1995a) ‘‘intra- granular activation’’ (Letourneau et al., 1996) or ‘‘piece- meal’’ degranulation (Dvorak et al., 1992a,b) . Such ‘‘subtle’’ activation may be associated with the ability of mast cells to release some mediators selectively (Kops et al., 0165-5728/$ - see front matter D 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2003.10.041 * Corresponding author. Department of Pharmacology and Experimen- tal Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. Tel.: +1-617-636-6866; fax: +1-617- 636-2456. E-mail address: theoharis.theoharides@tufts.edu (T.C. Theoharides). www.elsevier.com/locate/jneuroim Journal of Neuroimmunology 146 (2004) 1 – 12