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This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti\u2010inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10\u201314\u2009days transcranial PBM at 670\u2009nm (2 or 4\u2009J\/cm\n                    <jats:sup>2<\/jats:sup>\n                    \/day) or 904\u2009nm (4\u2009J\/cm\n                    <jats:sup>2<\/jats:sup>\n                    \/day) in young (3\u2009weeks) and older (15\u2009weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM\u2010induced changes in HS accumulation, astrocyte activation, CD206 (an anti\u2010inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near\u2010normalisation of microglial activation in older MPS IIIA mice by 904\u2009nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro\u2010inflammatory signalling through pSTAT1 and p\u2010p38 in NK and T cells in young but not older MPS IIIA mice (5\u2009weeks of age), and expansion of NK, B and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in older affected mice (17\u2009weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904\u2009nm PBM both reversed the Sanfilippo\u2010induced increase in pSTAT1 and p\u2010p38 expression in multiple leukocyte populations in young mice, while 904\u2009nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro\u2010inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16145-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16145","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T22:44:50Z","timestamp":1717800290000},"page":"2791-2813","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4485-7714","authenticated-orcid":false,"given":"A. 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