Dummies’ guide to the immune system in persistent pain. And why might exercise help?

This is a supplementary blog and dummies’ guide to a paper first published online in the BJSM in 2018. Smith BE, Hendrick P, Bateman M, et al. Musculoskeletal pain and exercise—challenging existing paradigms and introducing new British Journal of Sports Medicine 2019;53:907-912.

It formed part of a chapter in my recent PhD that looked at the assessment and management of patellofemoral pain. As such, my work is a product of supervision and collaboration.  So I would like to start by acknowledging and thanking my supervisors Pip Logan and Paul Hendrick, and collaborators Marcus BatemanSinead HoldenChris LittlewoodFiona MoffattMichael Rathleff, James Selfe and Toby Smith.


The previous blog ‘What is central sensitisation? A dummies’ guide to what it is and why might exercise help’ covered what central sensitisation is. This blog takes that further and attempts to give a dummies’ guide to how the immune system fits into pain, and how might exercise help for that.

For example, it is thought that the immune system may play an important role in chronic pain states. And may contribute to the development of hyperalgesia and allodynia (see the previous blog for a description of what they are) [1–3].

If you cause some damage to body tissues, it will typically result in the activation of inflammatory cells. With traditional signs and symptoms of inflammation, such as heat, swelling, redness to the skin and pain [4,5]. This process is activated by various substances, such as exposure to cell wall fragments, toxins or chemicals [5]. Typically these substances are detected by a family of receptors called pattern-recognition receptors and toll-like receptors [2]. Toll-like receptors are predominantly made up of glial cells and these sense the presence of damage that can be interpreted by the central nervous system [1,3].

blue and red abstract painting

This process by which the immune system is thought to influence pain (hyperalgesia and allodynia) is through alterations of the function of these glial cells. They stop acting normally on immune function and start to be capable of acting on the spinal cord as a nociceptor [6].  There is a chain of events that are thought to occur that triggers this change in function; for further details, check out our paper here Musculoskeletal pain and exercise—challenging existing paradigms and introducing new. This inflammatory process secretes more pain mediators, working on a positive feedback loop to maintain long-term pain states [1]. The full mechanisms are not fully understood, but it is thought to correlate and overlap with central sensitisation [1].

Why exercise?

It is well recognised that regular exercise reduces the risk of developing age-related illnesses, such as heart disease and diabetes [7–9].

But regular physical exercise also reduces susceptibility to viral and bacterial infections.


We’re not really sure. But it does suggest that exercise somehow improves the overall immune function [10,11]. Maybe decreasing age-associated immunosenescence [12], maybe improvements in the innate immune response [10], or maybe decreasing chronic inflammation [12]. For further details, check out our paper here Musculoskeletal pain and exercise—challenging existing paradigms and introducing new.

adventure athlete athletic daylight

How do we know this?

Studies examining immune cells in physically active individuals compared with physically inactive individuals found that those active participants have significantly lower immune system activity [13–16].  Exercise does results in the release of a range of immune system substances, such as epinephrine, cortisol, growth hormone, and prolactin [17].  It is thought these substances can reduce the immune system activity  [18], and consequently, the reversing of the positive feedback loop and a desensitisation of pain.

Anything else to consider?

As will be covered in the next blog in this series, pain-related fear is a common feature of MSK pain. Pain-related fear is associated with the area of the brain called the amygdala (linked to fear and the response to fear), and this links to other areas of the brain that play a role in the inflammatory response of the body [19,20]. For example, two functional MRI (fMRI) studies investigating brain and immune function during experimental periods of induced stress reported increased activity of the amygdala, with subsequent increases of inflammatory markers [21,22].

Exercise can be a helpful tool is the treatment of pain-related, such as fear-avoidance and kinesiophobia [23]. And exercise may help with a reduction of the threat perception and a reduction in the activity of the amygdala. If it does, it could lead to densentisiation of pain as a result a dampening down of the immune system.  More reading here Musculoskeletal pain and exercise—challenging existing paradigms and introducing new British Journal of Sports Medicine 2019;53:907-912.


I hope you’ve found this dummies’ guide to the immune system in persistent pain and principles of general exercise for the immune system helpful.

The next supplementary blogs in this series will cover the role of affective aspects of pain.


[1]         Deleo JA, Tanga FY, Tawfik VL. Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia. Neurosci 2004;10:40–52.

[2]         Guo L-H, Schluesener HJ. The innate immunity of the central nervous system in chronic pain: the role of Toll-like receptors. Cell Mol Life Sci 2007;64:1128.

[3]         Nicotra L, Loram LC, Watkins LR, Hutchinson MR. Toll-like receptors in chronic pain. Exp Neurol 2012;234:316–29.

[4]         Woods JA, Vieira VJ, Keylock KT. Exercise, inflammation, and innate immunity. Immunol Allergy Clin North Am 2009;29:381–93.

[5]         Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci 2005;6:521.

[6]         Thacker M, Moseley L. Pathophysiological Mechanisms of Chronic Pain. In: Corns J, editor. Routledge Handb. Philos. Pain, Routledge; 1 edition; 2017, p. 124–39.

[7]         Colbert LH, Visser M, Simonsick EM, Tracy RP, Newman AB, Kritchevsky SB, et al. Physical activity, exercise, and inflammatory markers in older adults: findings from the Health, Aging and Body Composition Study. J Am Geriatr Soc 2004;52:1098–104.

[8]         Stewart KJ. Role of exercise training on cardiovascular disease in persons who have type 2 diabetes and hypertension. Cardiol Clin 2004;22:569–86.

[9]         Blair SN, Cheng Y, Holder JS. Is physical activity or physical fitness more important in defining health benefits? Med Sci Sport Exerc 2001;33:S379–99.

[10]      Kohut ML, Senchina DS. Reversing age-associated immunosenescence via exercise. Exerc Immunol Rev 2004;10:41.

[11]      DiPenta JM, Green-Johnson J, Murphy RJL. Natural killer cells and exercise training in the elderly: a review. Can J Appl Physiol 2004;29:419–43.

[12]      Woods JA, Lowder TW, Keylock K. Can exercise training improve immune function in the aged? Ann N Y Acad Sci 2002;959:117–27.

[13]      Stewart LK, Flynn MG, Campbell WW, Craig BA, Robinson JP, McFarlin BK, et al. Influence of exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4. Brain Behav Immun 2005;19:389–97.

[14]      McFarlin BK, Flynn MG, Campbell WW, Stewart LK, Timmerman KL. TLR4 is lower in resistance-trained older women and related to inflammatory cytokines. Med Sci Sport Exerc 2004;36:1876–83.

[15]      McFarlin BK, Flynn MG, Campbell WW, Craig BA, Robinson JP, Stewart LK, et al. Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4. Journals Gerontol Ser A Biol Sci Med Sci 2006;61:388–93.

[16]      Flynn MG, McFarlin BK, Phillips MD, Stewart LK, Timmerman KL. Toll-like receptor 4 and CD14 mRNA expression are lower in resistive exercise-trained elderly women. J Appl Physiol 2003;95:1833–42.

[17]      Nieman DC. Current perspective on exercise immunology. Curr Sports Med Rep 2003;2:239–42.

[18]      Gleeson M, McFarlin B, Flynn M. Exercise and Toll-like receptors. Exerc Immunol Rev 2006;12:34–53.

[19]      Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D, et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci 2003;100:1920–5.

[20]      Kop WJ, Weissman NJ, Zhu J, Bonsall RW, Doyle M, Stretch MR, et al. Effects of acute mental stress and exercise on inflammatory markers in patients with coronary artery disease and healthy controls. Am J Cardiol 2008;101:767–73.

[21]      Muscatell KA, Dedovic K, Slavich GM, Jarcho MR, Breen EC, Bower JE, et al. Greater amygdala activity and dorsomedial prefrontal–amygdala coupling are associated with enhanced inflammatory responses to stress. Brain Behav Immun 2015;43:46–53.

[22]      Slavich GM, Way BM, Eisenberger NI, Taylor SE. Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci 2010;107:14817–22.

[23]      Smith BE, Hendrick P, Bateman M, Moffatt F, Rathleff MS, Selfe J, et al. A loaded self-managed exercise programme for patellofemoral pain: a mixed methods feasibility study. BMC Musculoskelet Disord 2019;20:129. doi:10.1186/s12891-019-2516-1.