Cannabinoid receptor 2 evolutionary gene loss makes parrots more susceptible to neuroinflammation

Abstract

In vertebrates, cannabinoids modulate neuroimmune interactions through two cannabinoid receptors (CNRs) conservatively expressed in the brain (CNR1, syn. CB1) and in the periphery (CNR2, syn. CB2). Our comparative genomic analysis indicates several evolutionary losses in the CNR2 gene that is involved in immune regulation. Notably, we show that the CNR2 gene pseudogenized in all parrots (Psittaciformes). This CNR2 gene loss occurred because of chromosomal rearrangements. Our positive selection analysis suggests the absence of any specific molecular adaptations in parrot CNR1 that would compensate for the CNR2 loss in the modulation of the neuroimmune interactions. Using transcriptomic data from the brains of birds with experimentally induced sterile inflammation we highlight possible functional effects of such a CNR2 gene loss. We compare the expression patterns of CNR and neuroinflammatory markers in CNR2 -deficient parrots (represented by the budgerigar, Melopsittacus undulatus and five other parrot species) with CNR2 -intact passerines (represented by the zebra finch, Taeniopygia guttata ). Unlike in passerines, stimulation with lipopolysaccharide resulted in neuroinflammation in the parrots linked with a significant upregulation of expression in proinflammatory cytokines (including interleukin 1 beta ( IL1B ) and 6 ( IL6 )) in the brain. Our results indicate the functional importance of the CNR2 gene loss for increased sensitivity to brain inflammation.

Understanding the evolution of immune genes in jawed vertebrates

“…The immune system is remarkably flexible in terms of gene gain and loss (Chattopadhyay et al, 2020;Colgan et al, 2021;Divín et al, 2022;Krchlíková et al, 2023;Parham & Moffett, 2013;Solbakken et al, 2016;Velová et al, 2018). For example, gadiform fish have lost the MHC class II genes, a loss which seems to have been subsequently compensated for by an expansion of MHC class I gene copy number (Malmstrøm et al, 2016).…”

“…A recent comparative study of rockfish (genus Sebastes ) showed that particularly long‐lived species have an expanded number of immune modulatory butyrophilin genes and proposed an adaptive role for the immunosuppressive function of these genes in the long lifespans of these fish (Kolora et al, 2021 ). The immune system is remarkably flexible in terms of gene gain and loss (Chattopadhyay et al, 2020 ; Colgan et al, 2021 ; Divín et al, 2022 ; Krchlíková et al, 2023 ; Parham & Moffett, 2013 ; Solbakken et al, 2016 ; Velová et al, 2018 ). For example, gadiform fish have lost the MHC class II genes, a loss which seems to have been subsequently compensated for by an expansion of MHC class I gene copy number (Malmstrøm et al, 2016 ).…”

Bacterial communities along parrot digestive and respiratory tracts: the effects of sample type, species and time

“…Whilst rarely studied, parrots represent an important group of widespread domestic animals with the potential to transmit microbial infections to humans (Jones et al 2014 ; Balsamo et al 2017 ; Nga et al 2019 ). Compared to other birds, parrots may suffer from impaired regulation of inflammation (Divín et al 2022 ), which could facilitate transmission of certain diseases. For example, pet parrots may be responsible for transmitting psittacosis, a bacterial infection caused by Chlamidia pssitaci (Balsamo et al 2017 ; Ravichandran et al 2021 ).…”